Institute of Pathology, University Medical Centre Mannheim and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
Institute of Pathology, University Medical Centre Mannheim and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
J Thorac Oncol. 2021 Jun;16(6):1003-1016. doi: 10.1016/j.jtho.2021.02.008. Epub 2021 Feb 17.
In-depth genomic characterization of thymic epithelial tumors (TETs), comprising thymomas and thymic carcinomas (TCs), failed to identify targetable mutations and suggested unique biology of TETs, including KIT expression in most TCs. Recently, tuft cell-like medullary thymic epithelial cells were identified in the murine thymus, and our reanalysis of the published gene expression data revealed that these cells express KIT. In addition, recently, a minor subset of SCLCs with tuft cell-like features was described.
We interrogated mRNA expression data from our tumor cohorts (N = 60) and publicly available, independent data sets from TETs and NSCLC (N = 1199) for expression of tuft cell genes and KIT. Expression of KIT and of POU2F3 protein, the master regulator of tuft cells, was analyzed in cancer tissue (N = 344) by immunohistochemistry.
Normal human thymic tuft cells and most TCs coexpressed KIT and known tuft cell genes, particularly POU2F3 and GFI1B. Unexpectedly, small subsets of tuft cell-like tumors coexpressing POU2F3, GFI1B, and KIT were also identified among pulmonary squamous cell carcinomas, adenocarcinomas, and large cell neuroendocrine carcinoma and clustered together in each histologic cohort. In addition to the tuft cell-like signature, both thymic and lung tuft cell-like carcinomas had distinct genetic, pathologic, and clinical features in each cohort.
We suggest that the tuft cell-like phenotype defines novel subsets of thymic and pulmonary carcinoma. Its high prevalence in thymic squamous cell carcinomas that have no known toxic or viral etiologies suggests a new mechanism of carcinogenesis that may lead to specific drug susceptibilities.
深入的胸腺瘤（包括胸腺癌和胸腺癌）的基因组特征分析未能鉴定出可靶向的突变，并提示胸腺瘤具有独特的生物学特性，包括大多数胸腺癌中 KIT 的表达。最近，在鼠胸腺中鉴定出了类簇细胞样的髓质胸腺上皮细胞，我们对已发表的基因表达数据的重新分析表明，这些细胞表达 KIT。此外，最近还描述了一小部分具有类簇细胞样特征的 SCLC。
我们对肿瘤队列（N=60）和来自 TETs 和 NSCLC 的公共独立数据集（N=1199）的 mRNA 表达数据进行了分析，以研究簇细胞基因和 KIT 的表达。通过免疫组织化学分析，对癌症组织（N=344）中 KIT 和 POU2F3 蛋白（簇细胞的主要调节因子）的表达进行了分析。
正常人类胸腺簇细胞和大多数胸腺瘤均共表达 KIT 和已知的簇细胞基因，特别是 POU2F3 和 GFI1B。出乎意料的是，在肺鳞状细胞癌、腺癌和大细胞神经内分泌癌中也发现了一小部分簇细胞样肿瘤，它们共同表达 POU2F3、GFI1B 和 KIT，并且在每个组织队列中聚集在一起。除了簇细胞样特征外，胸腺和肺簇细胞样癌在每个队列中都具有独特的遗传、病理和临床特征。
我们认为簇细胞样表型定义了胸腺癌和肺癌的新型亚型。在没有已知毒性或病毒病因的胸腺癌中，簇细胞样表型的高发生率提示了一种新的致癌机制，可能导致特定的药物敏感性。
